Why do we use 100†mg of clofazimine in TB and NTM treatment?

Current tuberculosis and non-tuberculous mycobacterial disease guidelines recommend the use of clofazimine in a 100 mg once-daily dose. The rationale behind this exact dose is not provided. I performed a literature review to determine the reasoning behind the current dosing regimen. The current 100 mg once-daily dose of clofazimine stems from a deliberate attempt to find the minimum effective daily dose in leprosy treatment, driven by efficacy, economical and toxicity considerations. While this dose is safe, economical and practical, a higher dose with a loading phase may add relevant efficacy and treatment-shortening potential to both tuberculosis and non-tuberculous mycobacterial disease treatment. We need to revisit dose-response and maximum tolerated dose studies to get the best out of this drug, while continuing efforts to generate more active r-iminophenazine molecules that accumulate less in skin and intestinal tissues and have pharmacokinetic properties that do not require loading doses.

Epidemiology and treatment outcomes of recurrent tuberculosis in Tanzania from 2018 to 2021 using the National TB dataset.

BACKGROUND: Patients with recurrent TB have an increased risk of higher mortality, lower success rate, and a relatively feeble likelihood of treatment completion than those with new-onset TB. This study aimed to assess the epidemiology of recurrent TB in Tanzania; specifically, we aim to determine the prevalence of TB recurrence and factors associated with unfavourable treatment outcomes among patients with recurrent TB in Tanzania from 2018 to 2021. METHODS: In this cross-sectional study, we utilized Tanzania's routinely collected national TB program data. The study involved a cohort of TB patients over a fixed treatment period registered in the TB and Leprosy case-based District Health Information System (DHIS2-ETL) database from 2018 to 2021 in Tanzania. We included patients' sociodemographic and clinical factors, facility characteristics, and TB treatment outcomes. We conducted bivariate analysis and multivariable multi-level mixed effects logistic regression of factors associated with TB recurrence and TB treatment outcomes to account for the correlations at the facility level. A purposeful selection method was used; the multivariable model included apriori selected variables (Age, Sex, and HIV status) and variables with a p-value <0.2 on bivariate analysis. The adjusted odds ratio and 95% confidence interval were recorded, and a p-value of less than 0.05 was considered statistically significant. FINDINGS: A total of 319,717 participants were included in the study; the majority were adults aged 25-49 (44.2%, n = 141,193) and above 50 years (31.6%, n = 101,039). About two-thirds were male (60.4%, n = 192,986), and more than one-fifth of participants (22.8%, n = 72,396) were HIV positive. Nearly two in every hundred TB patients had a recurrent TB episode (2.0%, n = 6,723). About 10% of patients with recurrent TB had unfavourable treatment outcomes (9.6%, n = 519). The odds of poor treatment outcomes were two-fold higher for participants receiving treatment at the central (aOR = 2.24; 95% CI 1.33-3.78) and coastal zones (aOR = 2.20; 95% CI 1.40-3.47) than the northern zone. HIV-positive participants had 62% extra odds of unfavourable treatment outcomes compared to their HIV-negative counterparts (aOR = 1.62; 95% CI 1.25-2.11). Bacteriological TB diagnosis (aOR = 1.39; 95% CI 1.02-1.90) was associated with a 39% additional risk of unfavourable treatment outcomes as compared to clinical TB diagnosis. Compared to community-based DOT, patients who received DOT at the facility had 1.39 times the odds of poor treatment outcomes (aOR = 1.39; 95%CI 1.04-1.85). CONCLUSION: TB recurrence in Tanzania accounts for 2% of all TB cases, and it is associated with poor treatment outcomes. Unfavourable treatment outcomes were recorded in 10% of patients with recurrent TB. Poor TB treatment outcome was associated with HIV-positive status, facility-based DOT, bacteriologically confirmed TB and receiving treatment at the hospital level, differing among regions. We recommend post-treatment follow-up for patients with recurrent TB, especially those coinfected with HIV. We also propose close follow-up for patients treated at the hospital facility level and strengthening primary health facilities in TB detection and management to facilitate early treatment initiation.

Deciphering drug discovery and microbial pathogenesis research in tuberculosis during the two decades of postgenomic era using entity mining approach.

We examined literature on Mycobacterium tuberculosis (Mtb) subsequent to its genome release, spanning years 1999-2020. We employed scientometric mapping, entity mining, visualization techniques, and PubMed and PubTator databases. Most popular keywords, most active research groups, and growth in quantity of publications were determined. By gathering annotations from the PubTator, we determined direction of research in the areas of drug hypersensitivity, drug resistance (AMR), and drug-related side effects. Additionally, we examined the patterns in research on Mtb metabolism and various forms of tuberculosis, including skin, brain, pulmonary, extrapulmonary, and latent tuberculosis. We discovered that 2011 had the highest annual growth rate of publications, at 19.94%. The USA leads the world in publications with 18,038, followed by China with 14,441, and India with 12,158 publications. Studies on isoniazid and rifampicin resistance showed an enormous increase. Non-tuberculous mycobacteria also been the subject of more research in effort to better understand Mtb physiology and as model organisms. Researchers also looked at co-infections like leprosy, hepatitis, plasmodium, HIV, and other opportunistic infections. Host perspectives like immune response, hypoxia, and reactive oxygen species, as well as comorbidities like arthritis, cancer, diabetes, and kidney disease etc. were also looked at. Symptomatic aspects like fever, coughing, and weight loss were also investigated. Vitamin D has gained popularity as a supplement during illness recovery, however, the interest of researchers declined off late. We delineated dominant researchers, journals, institutions, and leading nations globally, which is crucial for aligning ongoing and evolving landscape of TB research efforts. Recognising the dominant patterns offers important information about the areas of focus for current research, allowing biomedical scientists, clinicians, and organizations to strategically coordinate their efforts with the changing priorities in the field of tuberculosis research.

Cocrystallizing and Codelivering Complementary Drugs to Multidrugresistant Tuberculosis Bacteria in Perfecting Multidrug Therapy.

Bacteria cells exhibit multidrug resistance in one of two ways: by raising the genetic expression of multidrug efflux pumps or by accumulating several drug-resistant components in many genes. Multidrug-resistive tuberculosis bacteria are treated by multidrug therapy, where a few certain antibacterial drugs are administered together to kill a bacterium jointly. A major drawback of conventional multidrug therapy is that the administration never ensures the reaching of different drug molecules to a particular bacterium cell at the same time, which promotes growing drug resistivity step-wise. As a result, it enhances the treatment time. With additional tabletability and plasticity, the formation of a cocrystal of multidrug can ensure administrating the multidrug chemically together to a target bacterium cell. With properly maintaining the basic philosophy of multidrug therapy here, the synergistic effects of drug molecules can ensure killing the bacteria, even before getting the option to raise the drug resistance against them. This can minimize the treatment span, expenditure and drug resistance. A potential threat of epidemic from tuberculosis has appeared after the Covid-19 outbreak. An unwanted loop of finding molecules with the potential to kill tuberculosis, getting their corresponding drug approvals, and abandoning the drug after facing drug resistance can be suppressed here. This perspective aims to develop the universal drug regimen by postulating the principles of drug molecule selection, cocrystallization, and subsequent harmonisation within a short period to address multidrug-resistant bacteria.

Factors associated with tuberculosis treatment success among tuberculosis and human immunodeficiency virus co-infected patients in Kelantan.

INTRODUCTION: Tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection is a global public health issue among people living with HIV. The objective was to assess the prevalence of TB treatment outcomes (successful and unsuccessful) and associated factors with TB treatment success among TB and HIV co-infected patients in Kelantan for 5 years (2014-2018). The successful TB treatment was defined as the sum of cured patients and those who completed the treatment. The unsuccessful treatment was defined as the sum of treatment failed, died, and default. MATERIALS AND METHODS: A cross-sectional study was conducted at the TB/Leprosy Unit of the State Health Department of Kelantan (JKNK) using secondary data from January 2014 to December 2018 assessed in the MyTB online system. The data were analyzed using SPSS 25.0 and STATA 14. Ethics approvals were obtained from Medical Research Ethics Committee (MREC) and UniSZA Human Research Ethics Committee (UHREC). RESULTS: Kelantan had 6,313 TB cases from January 2014 to December 2018. There were 703 (11.1%) cases of TB and HIV co-infection. The prevalence of successful treatment among TB and HIV co-infected patients was 57.1%. The duration of treatment and anatomy of TB location was significantly associated with TB treatment success. CONCLUSION: This study's findings showed that the prevalence of TB treatment success rate was 57.1%, and the unsuccessful rate was 42.9%. The treatment duration and the TB location's anatomy were significantly associated with the treatment success rate. Improving TB treatment outcomes should be started with anti-TB treatment immediately after TB diagnosis. Therefore, the government should strengthen the TB/HIV collaborative efforts to achieve good treatment outcomes among these vulnerable patients.

Treatment outcomes of tuberculosis patients in a Directly Observed Treatment Short course (DOTS) Referral Centre in Delta State, Nigeria: a five-year review (2012 - 2016).

Introduction: The objective of this study is to observe the trend in treatment outcomes and identify determinants of treatment success among patients recruited into care through the DOTS strategy. Methodology: A retrospective record review of tuberculosis patients (2012-2016) was carried out at the Tuberculosis and Leprosy Referral Centre, Eku, Delta State, Nigeria. Results: Records of four hundred and twenty five (425) tuberculosis patients under DOTS were reviewed over five years. The highest number of cases under treatment, 102 (24.0%), was recorded in 2013. The mean age (SD) of patients was 37.3 (±16.5) years, majority of the patients were male (62.4%) and 18% had TB/HIV co-infection. Treatment outcomes of patients were cured (53.4%), completed (27.8%), died (6.8%), failed (2.4%), lost to follow up (4.9%), transferred out (1.2%) and not evaluated (3.5%). Over all, treatment success rate was 81.2% with a trend of 88.7% (2012), 87.3% (2013), 85.9% (2014), 65.0% (2015) and 65.8% (2016) respectively. Patient characteristics were not associated with treatment success. Conclusion: The treatment success rate was high and in line with the national recommendation of 80% and above. The trend showed a reduction in number of new cases enrolled into the DOTS programme, reduction in success rate with a concomitant increase in loss to follow up. There was no association between patient characteristics and TB treatment success. System strengthening on patient follow up, community health education and treatment adherence is recommended.

Telacebec: an investigational antibacterial for the treatment of tuberculosis (TB).

INTRODUCTION: Tuberculosis is an infectious disease that affected more than 50 million people and killed 6.7 million patients in the past 5 years alone. Additionally, rising incidence of treatment resistance threatens the global effort to eradicate this disease. With limited options available, additional novel antibiotics are needed for the treatment of multidrug-resistant tuberculosis (MDR-TB). Telacebec is a first-in-class antibiotic that targets the pathogen's energy metabolism. AREAS COVERED: This paper provides an overview of the recent progress in the development and testing of telacebec. We discuss published clinical data and examine the design and setup of its clinical trials. We also offer insights on the therapeutic potential of telacebec and aspects of which should be evaluated in the future. EXPERT OPINION: The first phase 2a trial showed a correlation between dosage and bacterial load in patient sputum, which should be confirmed using a direct measurement method such as colony-forming unit counting. Its clinical efficacy, favorable pharmacokinetic properties, low arrhythmogenic risk, and activity against MDR-TB strains make telacebec a suitable candidate for further development. Future clinical testing in combination with approved second-line drugs will reveal its full potential against MDR-TB. Considering recent preclinical studies, we also recommend initiating clinical trials for Buruli ulcer and leprosy.

Tools to develop antibiotic combinations that target drug tolerance in Mycobacterium tuberculosis.

Combination therapy is necessary to treat tuberculosis to decrease the rate of disease relapse and prevent the acquisition of drug resistance, and shorter regimens are urgently needed. The adaptation of Mycobacterium tuberculosis to various lesion microenvironments in infection induces various states of slow replication and non-replication and subsequent antibiotic tolerance. This non-heritable tolerance to treatment necessitates lengthy combination therapy. Therefore, it is critical to develop combination therapies that specifically target the different types of drug-tolerant cells in infection. As new tools to study drug combinations earlier in the drug development pipeline are being actively developed, we must consider how to best model the drug-tolerant cells to use these tools to design the best antibiotic combinations that target those cells and shorten tuberculosis therapy. In this review, we discuss the factors underlying types of drug tolerance, how combination therapy targets these populations of bacteria, and how drug tolerance is currently modeled for the development of tuberculosis multidrug therapy. We highlight areas for future studies to develop new tools that better model drug tolerance in tuberculosis infection specifically for combination therapy testing to bring the best drug regimens forward to the clinic.

Tuberculosis treatment within differentiated service delivery models in global HIV/TB programming.

INTRODUCTION: Providing more convenient and patient-centred options for service delivery is a priority within global HIV programmes. These efforts improve patient satisfaction and retention and free up time for providers to focus on new HIV diagnoses or severe illness. Recently, the coronavirus disease 2019 (COVID-19) pandemic precipitated expanded eligibility criteria for these differentiated service delivery (DSD) models to decongest clinics and protect patients and healthcare workers. This has resulted in dramatic scale-up of DSD for antiretroviral therapy, cotrimoxazole and tuberculosis (TB) preventive treatment. While TB treatment among people living with HIV (PLHIV) has traditionally involved frequent, facility-based management, TB treatment can also be adapted within DSD models. Such adaptations could include electronic tools to ensure appropriate clinical management, treatment support, adherence counselling and adverse event (AE) monitoring. In this commentary, we outline considerations for DSD of TB treatment among PLHIV, building on best practices from global DSD model implementation for HIV service delivery. DISCUSSION: In operationalizing TB treatment in DSD models, we consider the following: what activity is being done, when or how often it takes place, where it takes place, by whom and for whom. We discuss considerations for various programme elements including TB screening and diagnosis; medication dispensing; patient education, counselling and support; clinical management and monitoring; and reporting and recording. General approaches include multi-month dispensing for TB medications during intensive and continuation phases of treatment and standardized virtual adherence and AE monitoring. Lastly, we provide operational examples of TB treatment delivery through DSD models, including a conceptual model and an early implementation experience from Zambia. CONCLUSIONS: COVID-19 has catalysed the rapid expansion of differentiated patient-centred service delivery for PLHIV. Expanding DSD models to include TB treatment can capitalize on existing platforms, while providing high-quality, routine treatment, follow-up and patient education and empowerment.

Challenges and Opportunities of Nanotechnological based Approach for the Treatment of Tuberculosis.

Mycobacterium tuberculosis, because of its unique biochemical behavior and a complex host relationship, successfully evades the host immune system. Therefore, chemotherapy appears to be the first-line option for patients with tuberculosis. However, poor patient compliance with anti-tubercular treatment and variability in anti-tubercular drug pharmacokinetics are among the major driving factors for the emergence of drug resistance. The rising cases of extrapulmonary TB, cross-resistance patterns, high prevalence of tuberculosis and HIV co-infections make tuberculosis treatment more complicated than conventional multidrug therapy. Due to their distinct advantages like higher solubility, increased payload, controlled release profiles, tissue-specific accumulation, and lack of toxicity, nanoscale materials have immense potential for drug delivery applications. An appropriate selection of polymer and careful particle engineering further improves therapeutic outcomes with opportunities to overcome conventional anti-tubercular drugs' challenges. The present review introduces the prospect of using nanotechnology in tuberculosis (TB) chemotherapy and provides a comprehensive overview of recent advances in nanocarriers implied for delivering anti-tubercular drugs.

Treatment outcomes of drug susceptible Tuberculosis in private health facilities in Lagos, South-West Nigeria.

BACKGROUND: The Lagos State Tuberculosis, Buruli Ulcer, and Leprosy Control Program (LSTBLCP) started engaging private hospitals under the Public-Private Mix (PPM) Program in 2008. The study aimed to evaluate the trend and predictors of successful Tuberculosis (TB) treatment outcomes of patients managed across these private health facilities between 2010-2016 in Lagos, Nigeria. METHODS: Retrospective review of TB treatment register and treatment cards of patients commenced on TB treatment between January 2010 and December 2016 in 36 private health facilities engaged by the LSTBLCP. Between December 2016 and February 2017, data were collected and entered into Microsoft Excel by trained data entry clerks. The analysis was done using SPSS software. Independent predictors of successful treatment outcomes were determined using multivariate analysis at the statistical significance of p<0.05 and 95% confidence interval. RESULTS: A total of 1660 records of TB patients were reviewed. 1535 (92.47%) commenced treatment, while 1337 (87.10%) of all records had documented treatment outcomes. Of the 1337 patients with outcomes, 1044 (78.09%) had a successful treatment outcome, and 293 (21.91%) had an unsuccessful outcome. Majority were male, 980 (59.04%), Human Immunodeficiency Virus (HIV) negative status, 1295 (80.24%), diagnosed with smear, 1141 (73.14%), treated in private not-for-profit (PNFP) hospital, 1097 (66.08%), treated for TB between 2014-2016 (18.96%-19.52%). In multivariate analysis, age>20years (aOR = 0.26, p = 0.001), receiving TB treatment in 2013 (aOR = 0.39, p = 0.001), having genexpert for TB diagnosis (aOR = 0.26, p = 0.031) and being HIV positive (aOR = 0.37, p = 0.001) significantly reduced likelihood of successful treatment outcome. The site of TB, being on ART or CPT, were confounding determinants of successful treatment outcomes as they became non-significant at the multivariate analysis level. CONCLUSION: Treatment outcome among Lagos private hospitals was low compared with NTBLCP and World Health Organization (WHO) target. We urge the government and TB stakeholders to strengthen the PPM interventions to improve adherence, particularly among People Living with HIV (PLHIV) and older TB patients. Hence, promotion of early care-seeking, improving diagnostic and case holding efficiencies of health facilities, and TB/HIV collaborative interventions can reduce the risk of an unsuccessful outcome.

Adherence to the MDR-TB intensive phase treatment protocol amongst individuals followed up at central and peripheral health care facilities in Uganda - a descriptive study.

BACKGROUND: Following initiation of MDR-TB treatment, patients have a choice to receive follow up DOT supervision at either the central initiating facility or at a peripheral facility. OBJECTIVES: We describe the adherence patterns of MDR-TB patients undergoing DOT supervision at the two health facility categories during intensive phase of treatment. METHODS: We used a retrospective cohort of patients initiated on MDR TB treatment at Mulago National Referral Hospital between 2014 and 2016. We extracted data from the National Tuberculosis and Leprosy Program records and analysed these using STATA V14. RESULT: Majority (84.01%) of the patients received their DOT supervision from the peripheral facilities. Males made up 62.1% of patients, and 91.2% had had their household contacts screened for MDR-TB. 26.5% of the patients on peripheral DOT supervision had good adherence to treatment protocol compared to 0% among patients on central initiating health facility DOT supervision. Among the patients with good adherence, 24.1% had contacts screened for MDR-TB as compared to 3.6% with poor adherence. CONCLUSION: More patients preferred MDR-TB DOT supervision at peripheral facilities, which had better adherence to the treatment protocol compared to the central initiating facility. Younger people and those with household contacts screened had better adherence to the treatment protocol, highlighting areas for targeted interventional programs for MDR-TB in resource limited settingsMore patients preferred MDR-TB DOT supervision at peripheral facilities, which had better adherence to the treatment protocol compared to the central initiating facility. Younger people and those with household contacts screened had better adherence to the treatment protocol, highlighting areas for targeted interventional programs for MDR-TB in resource limited settings.

Prediction of rifampicin resistance beyond the RRDR using structure-based machine learning approaches.

Rifampicin resistance is a major therapeutic challenge, particularly in tuberculosis, leprosy, P. aeruginosa and S. aureus infections, where it develops via missense mutations in gene rpoB. Previously we have highlighted that these mutations reduce protein affinities within the RNA polymerase complex, subsequently reducing nucleic acid affinity. Here, we have used these insights to develop a computational rifampicin resistance predictor capable of identifying resistant mutations even outside the well-defined rifampicin resistance determining region (RRDR), using clinical M. tuberculosis sequencing information. Our tool successfully identified up to 90.9% of M. tuberculosis rpoB variants correctly, with sensitivity of 92.2%, specificity of 83.6% and MCC of 0.69, outperforming the current gold-standard GeneXpert-MTB/RIF. We show our model can be translated to other clinically relevant organisms: M. leprae, P. aeruginosa and S. aureus, despite weak sequence identity. Our method was implemented as an interactive tool, SUSPECT-RIF (StrUctural Susceptibility PrEdiCTion for RIFampicin), freely available at https://biosig.unimelb.edu.au/suspect_rif/ .

Coexistence of mycobacterial infections - Mycobacterium tuberculosis and Mycobacterium leprae - in Sri Lanka: a case series.

BACKGROUND: Leprosy is one of the oldest mycobacterial infections and tuberculosis is the most common mycobacterial infection with a higher degree of infectivity than leprosy. Although both diseases are prevalent in clusters in developing countries, simultaneous occurrence of them in an individual is a rare entity, even in an endemic setting. CASE PRESENTATION: We describe six cases of tuberculosis and leprosy coinfection: a 57-year-old Sinhalese woman, a 47-year-old Tamil woman, a 72-year-old Tamil man, a 59-year-old Sinhalese man, a 54-year-old Sinhalese man, and a 50-year-old Sinhalese man. In this case series, five patients had lepromatous leprosy and the majority of patients were men. Three patients were detected to have tuberculosis at the outset of treatment of leprosy, while two developed tuberculosis later and one had extrapulmonary tuberculosis 5 years before the diagnosis of leprosy. The latter developed pulmonary tuberculosis as a reactivation while on treatment for leprosy. A majority of our patients with pulmonary tuberculosis had positive Mantoux test, high erythrocyte sedimentation rate, radiological evidence, and acid-fast bacilli in sputum. Human immunodeficiency virus and diabetes were detected in one patient. One patient had rifampicin-resistant tuberculosis, while she was on monthly rifampicin therapy for leprosy. CONCLUSION: An immunocompromised status, such as human immunodeficiency virus infection, diabetes, and immunosuppressive drugs, are risk factors for tuberculosis infection. The use of steroids in the treatment of leprosy may increase the susceptibility to develop tuberculosis. Development of rifampicin resistance secondary to monthly rifampicin in leprosy is a major concern in treating patients coinfected with tuberculosis. Despite the paucity of reports of coinfection, it is advisable to screen for tuberculosis in patients with leprosy, especially if there are respiratory or constitutional symptoms, high erythrocyte sedimentation rate, and abnormal chest X-ray. The fact is that positive Mantoux and QuantiFERON Gold tests and presence of acid-fast bacilli in sputum are misleading, chest X-ray evidence of active tuberculosis and positive tuberculosis cultures are important diagnostic clues for active tuberculosis infection in a patient with leprosy. This is important to avoid monthly rifampicin in patients with suspected coinfections, which may lead to development of drug resistance to tuberculosis treatment. Whether prolonged steroid therapy in leprosy is a risk factor for development of tuberculosis is still controversial.

Cytological diagnosis in a clinically unsuspected case of disseminated BCGosis: A case report.

Bacille Calmette-Guerin (BCG) vaccine is administered worldwide to neonates and considered safe. Serious complications like disseminated BCGosis are extremely rare occurrences (<1 per million vaccinations). A 6 months male was brought to paediatric outpatient department with fever and swelling over the dorsum of the left hand for 5 days. On examination, he was febrile and had hepatosplenomegaly. X-ray of the hand showed lytic lesions in the first and second metacarpals. Provisional clinical diagnosis included Langerhans cell histiocytosis, congenital syphilis, and haematological malignancy. Fine Needle Aspiration Cytology (FNAC) was done from the swelling and showed diffuse sheets of histiocytes with both intracellular and extracellular rod-shaped unstained structures along with inflammatory cells. These ghost images stained positive with ZN stain. A cytological diagnosis of atypical mycobacteria vs leprosy was made. Child was revisited and found to have an active BCG scar. Further investigations showed low serum IgM and positive AFB culture. These bacilli were confirmed by GenoType MTBDR plus test as Mycobacterium bovis. Despite Antitubercular therapy, the patient succumbed to death. This case highlights the variable clinical presentation of BCGosis. Its occurrence may unmask any underlying immunodeficiency. If unfamiliar with the above cytological features and in absence of routinely performed special stains, the cytopathologist may miss these notorious organisms and treat such cases like suppurative lesions. To conclude, an early and definitive diagnosis of BCGosis can be established on FNAC which would ensure timely management and better outcome in this highly lethal entity.

Infect and Inject: How Mycobacterium tuberculosis Exploits Its Major Virulence-Associated Type VII Secretion System, ESX-1.

Mycobacterium tuberculosis is an ancient master of the art of causing human disease. One important weapon within its fully loaded arsenal is the type VII secretion system. M. tuberculosis has five of them: ESAT-6 secretion systems (ESX) 1 to 5. ESX-1 has long been recognized as a major cause of attenuation of the FDA-licensed vaccine Mycobacterium bovis BCG, but its importance in disease progression and transmission has recently been elucidated in more detail. This review summarizes the recent advances in (i) the understanding of the ESX-1 structure and components, (ii) our knowledge of ESX-1's role in hijacking macrophage function to set a path for infection and dissemination, and (iii) the development of interventions that utilize ESX-1 for diagnosis, drug interventions, host-directed therapies, and vaccines.

Arylvinylpiperazine Amides, a New Class of Potent Inhibitors Targeting QcrB of Mycobacterium tuberculosis.

New drugs are needed to control the current tuberculosis (TB) pandemic caused by infection with Mycobacterium tuberculosis We report here on our work with AX-35, an arylvinylpiperazine amide, and four related analogs, which are potent antitubercular agents in vitro All five compounds showed good activity against M. tuberculosisin vitro and in infected THP-1 macrophages, while displaying only mild cytotoxicity. Isolation and characterization of M. tuberculosis-resistant mutants to the arylvinylpiperazine amide derivative AX-35 revealed mutations in the qcrB gene encoding a subunit of cytochrome bc1 oxidase, one of two terminal oxidases of the electron transport chain. Cross-resistance studies, allelic exchange, transcriptomic analyses, and bioenergetic flux assays provided conclusive evidence that the cytochrome bc1-aa3 is the target of AX-35, although the compound appears to interact differently with the quinol binding pocket compared to previous QcrB inhibitors. The transcriptomic and bioenergetic profiles of M. tuberculosis treated with AX-35 were similar to those generated by other cytochrome bc1 oxidase inhibitors, including the compensatory role of the alternate terminal oxidase cytochrome bd in respiratory adaptation. In the absence of cytochrome bd oxidase, AX-35 was bactericidal against M. tuberculosis Finally, AX-35 and its analogs were active in an acute mouse model of TB infection, with two analogs displaying improved activity over the parent compound. Our findings will guide future lead optimization to produce a drug candidate for the treatment of TB and other mycobacterial diseases, including Buruli ulcer and leprosy.IMPORTANCE New drugs against Mycobacterium tuberculosis are urgently needed to deal with the current global TB pandemic. We report here on the discovery of a series of arylvinylpiperazine amides (AX-35 to AX-39) that represent a promising new family of compounds with potent in vitro and in vivo activities against M. tuberculosis AX compounds target the QcrB subunit of the cytochrome bc1 terminal oxidase with a different mode of interaction compared to those of known QcrB inhibitors. This study provides the first multifaceted validation of QcrB inhibition by recombineering-mediated allelic exchange, gene expression profiling, and bioenergetic flux studies. It also provides further evidence for the compensatory role of cytochrome bd oxidase upon QcrB inhibition. In the absence of cytochrome bd oxidase, AX compounds are bactericidal, an encouraging property for future antimycobacterial drug development.

Impact of community-based adherence support on treatment outcomes for tuberculosis, leprosy and HIV/AIDS-infected individuals in post-Ebola Liberia.

BACKGROUND: Partners In Health (PIH) committed to improving health care delivery in Maryland County, Liberia following the Ebola epidemic by employing 71 community health workers (CHWs) to provide treatment support to tuberculosis (TB), HIV and leprosy patients. PIH simultaneously deployed a socioeconomic assistance program with three core components: transportation reimbursement to clinics; food support; and additional social assistance in select cases. OBJECTIVE: This study aimed to evaluate how a CHW program for community treatment support and addressing socioeconomic barriers to care can impact patient outcomes in a post-conflict and post-epidemic context. METHODS: Retrospective observational study utilizing registry data from 513 TB, 447 HIV and 75 leprosy patients at three health facilities in Maryland County, Liberia. Treatment coverage and clinical outcomes for patient cohorts enrolled in the pre-intervention period (January 2015 to June 2015) and the post-intervention period (July 2015 to July 2017) are compared using logistic regression analyses. RESULTS: TB treatment coverage increased from 7.7% pre-intervention to 43.2% (p < 0.001) post-intervention and lost to follow-up (LTFU) rates decreased from 9.5% to 2.1% (p = 0.003). ART treatment coverage increased 3.8 percentage points (p = 0.03), with patient retention improving 63.9% to 86.1% (p < 0.001); a 6.0 percentage point decrease in HIV LTFU was also observed (p = 0.21). Despite an 84.3% treatment success rate observed for leprosy patients, pre-intervention data was largely unavailable and statistical significance could not be reached for any treatment outcomes pre-post intervention. CONCLUSIONS: The PIH approach to CHW community treatment support in Liberia demonstrates how, with the right inputs, excellent clinical outcomes are possible even in post-conflict and post-epidemic contexts. Care should be taken to position and support CHWs so that they have the opportunity to succeed, including full integration and recognition within the system, and the addition of clinical system improvements and social supports that are too often dismissed as unsustainable.

Treatment outcome of tuberculosis among Human Immunodeficiency Virus positive patients in Eastern Ethiopia: a retrospective study.

INTRODUCTION: Tuberculosis is the leading cause of morbidity and mortality among people living with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome worldwide. Although Human Immunodeficiency Virus related tuberculosis is both treatable and preventable, incidence rates continue to climb in developing countries where both infections are endemic. The aim of this study was to assess the treatment outcome of tuberculosis among Human Immunodeficiency Virus positive patients attending in three hospitals of Eastern Ethiopia. METHODS: A retrospective clinical record review was conducted for 627 Tuberculosis and Human immunodeficiency virus co-infected patients registered from January 2008 to January 2014 cards were reviewed in three hospitals of tuberculosis clinics of Eastern Ethiopia from December 2015 to February 2016. The three hospitals were selected based on their high patient load of TB-HIV co infection and the presence of ART and TB units. Data on patient's details and tuberculosis treatment outcome were collected using standardized report format of National Tuberculosis and Leprosy Control Programme (NTLCP). The collected data were analyzed by Statistical Package for Social Sciences (SPSS) software Version 16. RESULTS: The overall treatment success rate was 78.3%. Of the total TB-HIV co infected study participants, 17.9% cured, 60.4% treatment completed, 8.6% died, 0.6% failure, 1.8% defaulter and 10.7% transferred out. Those participants in the age groups of less than or equals to 18 years old (Adjusted Odds Ratio = 1.990, 95% Confidence Interval: 1.01, 3.350), extra pulmonary tuberculosis (Adjusted Odds Ratio = 1.51, 95% Confidence Interval = 1.12, 3.42), on antiretro viral therapy (Adjusted Odds Ratio = 1.54, 95% Confidence Interval = 1.252, 3.910) were more likely to have higher treatment outcome than each of the above variables counter parts. CONCLUSION: The rate of treatment success in this study was lower than recommended rate by World Health Organization. Thus this study recommends improving counseling during tuberculosis treatment, providing home visits and motivation of patients, improving defaulter tracing and health information dissemination in order to reduce treatment interruption.

Treatment outcomes of tuberculosis patients under directly observed treatment short-course at Debre Tabor General Hospital, northwest Ethiopia: nine-years retrospective study.

BACKGROUND: Data regarding tuberculosis (TB) treatment outcomes, proportion of TB/HIV co-infection and associated factors have been released at different TB treatment facilities in Ethiopia and elsewhere in the world as part of the auditing and surveillance service. However, these data are missing for the TB clinic offering directly observed treatment short-course (DOTs) at Debre Tabor General Hospital (DTGH). METHODS: The authors analysed the records of 985 TB patients registered at the DTGH from September 2008 to December 2016. Data on patients' sex, age, type of TB, and treatment outcomes were extracted from the TB treatment registration logbook. The treatment outcome of patients was categorized according to the National TB and Leprosy Control Program guidelines: cured, treatment completed, treatment failed, died, and not evaluated (transferred out and unknown cases). RESULTS: Around half of the registered patients were males (516, 52.4%). In terms of TB types, 381 (38.7%), 241 (24.5%), and 363 (36.9%) patients had smear-negative pulmonary TB, smear-positive pulmonary TB, and extra pulmonary TB, respectively. Six hundred and seventy-two patients (90.1%) had successful treatment outcomes (cured and treatment completed), while 74 patients (9.9%) had unsuccessful treatment outcomes (death and treatment failure).TB treatment outcome was not associated with age, sex, type and history of TB, or co-infection with HIV (P > 0.05). The proportion of TB/HIV co-infection was at 24.2%, and these were found to be significantly associated with the age groups of 25-34, 35-44 and ≥65 years:(aOR: 0.44; 95% CI: 0.25-0.8), (aOR: 0.39; 95% CI: 0.20-0.70), (aOR: 4.2; 95% CI: 1.30-12.9), respectively. CONCLUSIONS: The proportion of patients with successful treatment outcomes was above the World Health Organization target set for Millennium Development Goal of 85% and in line with that of the global milestone target set at > 90% for 2025. Relatively higher proportions of transfer-out cases were recorded in the present study. Similarly, the proportion of TB/HIV co-infection cases was much higher than the national average of 8%.Thus, the health facility under study should develop strategies to record the final treatment outcome of transfer-out cases. In addition, strategies to reduce the burden of TB/HIV co-infection should be strengthened.